IMPORTANCE Neuroprotective and remyelinating therapies are required for multiple sclerosis (MS), and acute optic neuritis (AON) is a potential condition to evaluate such treatments.OBJECTIVE To comprehensively assess key biological and methodological aspects of AON trials for testing neuroprotection and remyelination in MS.

Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), wholebrain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium-enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p < 0.001). Thereafter, rates of retinal and brain changes stabilized and were similar in active and stable patients. Focal inflammatory activity is associated with neurodegeneration early in MS which reinforces the use of an early intensive anti-inflammatory therapy to prevent neurodegeneration in MS. Abbreviations 95% CI 95% confidence interval AIC Akaike information criterion CIS Clinically isolated syndrome CNS Central nervous system DMD Disease-modifying drug FLAIR Fluid-attenuated inversion recovery Gad+ Gadolinium enhancing lesions GCIPL Ganglion cell plus inner plexiform layer MPRAGE Magnetisation prepared rapid acquisition gradient echo MRI Magnetic resonance imaging

Background Several studies have suggested that the retina structure is affected in schizophrenia spectrum disorders (SSD). We aimed to investigate the location and size of the potential differences between patients and healthy controls (HC) in several thickness and volume measures across the retina Study Design We included cross-sectional studies comparing peripapillary retinal nerve fiber layer (pRNFL) thickness, macular volume, macular thickness (MT), foveal thickness, ganglion cell and inner plexiform layer thickness (GCL+IPL), cup volume, and cup/disc ratio (C/D) in the right and/or left eyes and/or the pRNFL and MT quadrants between patients with SSD and HC. Search databases were MEDLINE, Web of Science, PsycINFO, Cochrane Central, and medrxiv.org. Risk of bias was assessed with the Newcastle-Ottawa Scale. Standardized mean differences (SMD), subgroup analysis, and meta-regression with several variables were computed using the dmetar package in R. PROSPERO: CRD42021287873. Study Results Data from 22 reports (942 patients, 742 HC) were included. We found a retinal thinning in pRNFL (−0.30; 95% CI: −0.46, −0.14), macula (−0.37; 95% CI: −0.61, −0.13), and GCL+IPL (−0.33; 95% CI: −0.57, −0.10). The retinal thinning was especially pronounced in the superior and inferior quadrants of the inner ring of the macula. We also observed a decrease of macular volume (−0.44; 95% CI: −0.68, −0.20) and an increase in C/D ratio (0.35; 95% CI: 0.03, 0.67). Conclusions Current evidence demonstrates retinal thinning in SSD, affecting both axonal and cellular structures, specially focused in the inner ring of the macula.